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While prostate multiparametric-magnetic resonance imaging (MP-MRI) has improved the diagnosis of clinically significant prostate cancer (CSPC), the complementary use of prostate-specific antigen (PSA) levels to risk-stratify for CSPC requires further study. The objective of this project was to determine if prostate MP-MRI and PSA can provide complementary insights into CSPC risk stratification.In an IRB-approved study, pathologic outcomes from patients who underwent MR/US fusion-targeted prostate biopsy were stratified by various parameters including PSA, PSA density (PSAD), age, race, and PI-RADS v2 score. CSPC was defined as a Gleason score ≥7. Logistic regression was used to determine odds ratios (OR) with 95% confidence intervals (CI). P values were reported as two-sided with p 0.05 considered statistically significant. ROC curves were generated for assessing the predictive value of tests and sensitivity + specificity optimization was performed to determine optimal testing cutoffs.A total of 327 patients with 709 lesions total were analyzed. PSAD and PI-RADS scores provided complementary predictive value for diagnosis of CSPC (AUC PSAD: 0.67, PI-RADS: 0.72, combined: 0.78, p 0.001). When controlling for PI-RADS score, age, and race, multivariate analysis showed that PSAD was independently associated with CSPC (OR 1.03 per 0.01 PSAD increase, 95% CI 1.02-105, p 0.001). The optimal cutoff of PSAD ≥ 0.1 ng/ml/cc shows that a high versus low PSAD was roughly equivalent to an increase in 1 in PI-RADS score for the presence of CSPC (4% of PI-RADS ≤3 PSAD low, 6% of PI-RADS 3 PSAD high vs. 5% of PI-RADS 4 PSAD low, 22% of PI-RADS 4 PSAD high vs. 29% of PI-RADS 5 PSAD low, 46% of PI-RADS 5 PSAD high were found to have CSPC).PSAD with a cutoff of 0.1 ng/ml/cc appears to be a useful marker that can stratify the risk of CSPC in a complementary manner to prostate MP-MRI.